Moving towards precision orthodontics: An evolving paradigm shift in the planning and delivery of customized orthodontic therapy.

Advances in precision medicine portend similar progress in orthodontics and will be increasingly harnessed to achieve customized treatment approaches and enhance treatment efficiencies. Our goal is to provide a background on emerging advances in computer technologies and biomedicine and highlight their current and likely future applications to precision orthodontics. A review of orthodontically relevant technologies and advances in pertinent biological research was undertaken. Innovations in computer hardware and software, and 3D imaging technologies offer the ability for customized treatment and biomechanical planning that will be more fully realized within the next few decades. These technologies combined with 3D printing are already being applied to customized appliance fabrication such as aligners and retainers. The future prospects for custom fabrication of orthodontic brackets of appropriate material properties and smart devices are highly desirable and compelling goals. Within biomedicine, the fundamental understanding of cartilage growth and bone biology is currently being tested in animal models to modify mandibular growth and modulate tooth movement, respectively. Some of these discoveries will ultimately have clinical applications in orthodontics including for growth modification, accelerating orthodontic tooth movement, and enhancing anchorage or retention of teeth. Additional genomic and proteomic information will add to further customization of orthodontic diagnosis and treatments. Over the coming decades, precision orthodontics will continue to benefit from advances in many fields and will require the integration of advances in technology, and biomedical and clinical research to deliver optimal, efficient, safe, and reproducible personalized orthodontic treatment.

Micro-anatomical responses in periodontal complexes of mice to calibrated orthodontic forces on the crown.

OBJECTIVE: Correlating mechanical forces with quantifiable physical changes in the dentoalveolar complex. SETTING AND SAMPLE POPULATION: Male 6-week C57BL/6 mice (N=3), micro X-ray-computed tomography; post-analysis software to extract physical changes in periodontal ligament (PDL)-space. MATERIALS AND METHODS: Silicone-elastic bands were placed between maxillary molars for 1 week, with the contralateral side as internal control. Average displacements between crowns and roots, and changes in PDL-spaces were evaluated by registering X-ray tomograms of experimental and control hemi-maxillae. Histology illustrated mineral formation and resorption-related events within narrowed and widened volumes of the PDL-space. RESULTS: 3D maps of changes in PDL-space between molars illustrated coronal and root displacements of 640 µm and 180 µm, respectively, compared to 70 µm in controls. Orthodontic tooth movement (OTM) specimens exhibited an average net change of -20 µm in narrowed and +30 µm in widened PDL-spaces. Bone and cementum were affected by the force on molars, and primary cementum was more affected than secondary cementum. CONCLUSIONS: This novel approach illustrates the importance of 3D-imaging and analysing 3D alveolar socket subjected to OTM otherwise omitted by 2D micrographs. A measured force on the crown elicits a response related to narrowed and widened regions in the 3D complex. OTM that exceeds PDL-space can illicit biological responses that attempt to restore physiologic PDL-space via remodelling of the periodontium. Regenerated weaker bone due to aseptic inflammation caused by orthodontics could leave patients at a higher risk of bone loss or root resorption if they later develop periodontitis, a form of septic inflammation.

Ras Signaling Regulates Stem Cells and Amelogenesis in the Mouse Incisor.

The role of Ras signaling during tooth development is poorly understood. Ras proteins-which are activated by many upstream pathways, including receptor tyrosine kinase cascades-signal through multiple effectors, such as the mitogen-activated protein kinase (MAPK) and PI3K pathways. Here, we utilized the mouse incisor as a model to study how the MAPK and PI3K pathways regulate dental epithelial stem cells and amelogenesis. The rodent incisor-which grows continuously throughout the life of the animal due to the presence of epithelial and mesenchymal stem cells-provides a model for the study of ectodermal organ renewal and regeneration. Utilizing models of Ras dysregulation as well as inhibitors of the MAPK and PI3K pathways, we found that MAPK and PI3K regulate dental epithelial stem cell activity, transit-amplifying cell proliferation, and enamel formation in the mouse incisor.

The cells that fill the bill: neural crest and the evolution of craniofacial development.

Avian embryos, which have been studied scientifically since Aristotle, continue to persevere as invaluable research tools, especially for our understanding of the development and evolution of the craniofacial skeleton. Whether the topic is beak shape in Darwin's finches or signaling interactions that underlie bone and tooth formation, birds offer advantages for craniofacial biology that uniquely complement the strengths of other vertebrate model systems, such as fish, frogs, and mice. Several papers published during the past few years have helped pinpoint molecular and cellular mechanisms that pattern the face and jaws through experiments that could only have been done together with our feathered friends. Ultimately, such knowledge will be essential for devising novel clinical approaches to treat and/or prevent diseases, injuries, and birth defects that affect the human craniofacial skeleton. Here we review recent insights plucked from avians on key developmental processes that generate craniofacial diversity.

Characterization of a novel KRAB/C2H2 zinc finger transcription factor involved in bone development.

Osteogenic differentiation involves a cascade of coordinated gene expression that regulates cell proliferation and matrix protein formation in a defined temporo-spatial manner. Here we have used differential display to identify a novel zinc finger transcription factor (AJ18) that is induced during differentiation of bone cells in vitro and in vivo. The 64-kDa protein, encoded by a 7- kilobase mRNA, contains a Krüppel-associated box (KRAB) domain followed by 11 successive C(2)H(2) zinc finger motifs. AJ18 mRNA, which is also expressed in kidney and brain, is developmentally regulated in embryonic tibiae and calvariae, with little expression in neonate and adult animals. During osteogenic differentiation in vitro AJ18 mRNA is expressed as cells approach confluence and declines as bone formation occurs. Using bacterially expressed, His-tagged AJ18 in a target detection assay, we identified a consensus binding sequence of 5'-CCACA-3', which forms part of the consensus element for Runx2, a master gene for osteogenic differentiation. Overexpression of AJ18 suppressed Runx2-mediated transactivation of an osteocalcin promoter construct in transient transfection assays and reduced alkaline phosphatase activity in bone morphogenetic protein-induced C3H10T1/2 cells. These studies, therefore, have identified a novel zinc finger transcription factor in bone that can modulate Runx2 activity and osteogenic differentiation.

The immune regulatory protein B7-H3 promotes osteoblast differentiation and bone mineralization.

B7-H3, a member of the B7 family of the Ig superfamily proteins, is expressed on the surface of the antigen-presenting cells and down-regulates T cell functions by engaging an unknown counterreceptor on T cells. Although B7-H3 is ubiquitously expressed, its potential nonimmune functions have not been addressed. We found that B7-H3 is highly expressed in developing bones during embryogenesis and that its expression increases as osteoblast precursor cells differentiate into mature osteoblasts. In vitro bone formation by osteoblastic cells was inhibited when B7-H3 function was interrupted by the soluble recombinant protein B7-H3-Fc. Analysis of calvarial cells derived from neonatal B7-H3 knockout (KO) mice revealed normal numbers of osteoblast precursor cells possessing a normal proliferative capacity. However, the B7-H3-deficient calvarial cells exhibited impaired osteogenic differentiation, resulting in decreased mineralized bone formation in vitro. These results suggest that B7-H3 is required for the later phase of osteoblast differentiation. Although B7-H3 KO mice had no gross skeletal abnormalities, they displayed a lower bone mineral density in cortical (but not trabecular) bones compared with WT controls. Consistent with the reduced bone mineral density, the femurs of B7-H3 KO mice were more susceptible to bone fracture compared with those of WT mice. Taken together, these results indicate that B7-H3 and its unknown counterreceptor play a positive regulatory role in bone formation. In addition, our findings identified B7-H3 as another molecule that has a dual role in the bone-immune interface.